The Center for Disease Control estimates that over two million Americans suffer traumatic brain injury each year and, of them, around 70,000 suffer permanent disability. The proposed research will evaluate the effectiveness of vagus nerve stimulation (VNS) as a treatment for brain injury. Stimulation of the vagus is known to have anti-seizure properties and it also facilitates neural plasticity as seen in its capacity to enhance memory storage. The proposed research will use the fluid percussion model of traumatic brain injury in rats to evaluate the capacity of VNS to facilitate recovery of function. This technique produces reliable and reproducible brain damage and the time course of recovery of animals that receive chronic vagus nerve stimulation and control animals will be evaluated on neurological tests such as spontaneous forelimb placing, beam walk, a skilled forelimb reaching task and a spatial localization task. Pilot data is presented which demonstrates that VNS produces enhanced behavioral recovery in some tasks; however, additional information, such as the frequency and intensity of VNS that is most effective, as well as the temporal window of therapeutic effectiveness, neuroanatomical sequelae and the mechanism(s) of the effectiveness of VNS in promoting recovery remain unknown and are specifically addressed in this proposal. Fluid percussion injury is known to cause a progressive loss of cortical and subcortical neurons, as well as a loss of GABA motor neurons in the cortex adjacent to the site of injury and in the hilar region of the hippocampus. Experiments will be performed to determine whether VNS following head injury attenuates cell loss in these regions. These studies will use quantitative morphometry as well as immunocytochemistry for glutamic acid decarboxylase and GABA. Finally, in an effort to understand the mechanism(s) that mediate the effects of VNS on recovery, severing the vagus afferents or efferents, in vivo microdialysis of regional levels of norepinephrine following fluid percussion injury and VNS, neurotoxic lesions of the locus coeruleus, and specific noradrenergic receptor antagonists will be used in order to determine how they influence the ability of VNS to enhance recovery. The combination of all of these aims will result in determining whether vagus nerve stimulation might be a useful treatment in promoting recovery following traumatic brain injury, as well as provide specific information about the neural mechanism(s) involved.